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Title: | Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis | Authors: | Savic, Nevena Markelić, Milica Stancic, Ana Veličković, Ksenija Grigorov, Ilijana Vucetic, Milica Martinovic, Vesna Gudelj, Andjelija Otasevic, Vesna |
Keywords: | GSH metabolism;Nrf2;diabetes;ferritinophagy;ferroptosis;iron metabolism;liver pathology;sulforaphane | Issue Date: | 1-Feb-2024 | Rank: | M21 | Publisher: | IUBMB Journals | Project: | The Ministry of Science, Technological Development and Innovation of the Republic of Serbia Science Fund of the Republic of Serbia (Serbian Science andDiaspora Collaboration Program: Knowledge ExchangeVouchers, Ferroptosis in the b-cells death: possible strategy for diabetes treatment, acronym:BetFeSis) |
Journal: | BioFactors (Oxford, England) | Abstract: | Recently, we characterized the ferroptotic phenotype in the liver of diabetic mice and revealed nuclear factor (erythroid-derived-2)-related factor 2 (Nrf2) inactivation as an integral part of hepatic injury. Here, we aim to investigate whether sulforaphane, an Nrf2 activator and antioxidant, prevents diabetes-induced hepatic ferroptosis and the mechanisms involved. Male C57BL/6 mice were divided into four groups: control (vehicle-treated), diabetic (streptozotocin-induced; 40 mg/kg, from Days 1 to 5), diabetic sulforaphane-treated (2.5 mg/kg from Days 1 to 42) and non-diabetic sulforaphane-treated group (2.5 mg/kg from Days 1 to 42). Results showed that diabetes-induced inactivation of Nrf2 and decreased expression of its downstream antiferroptotic molecules critical for antioxidative defense (catalase, superoxide dismutases, thioredoxin reductase), iron metabolism (ferritin heavy chain (FTH1), ferroportin 1), glutathione (GSH) synthesis (cystine-glutamate antiporter system, cystathionase, glutamate-cysteine ligase catalitic subunit, glutamate-cysteine ligase modifier subunit, glutathione synthetase), and GSH recycling - glutathione reductase (GR) were reversed/increased by sulforaphane treatment. In addition, we found that the ferroptotic phenotype in diabetic liver is associated with increased ferritinophagy and decreased FTH1 immunopositivity. The antiferroptotic effect of sulforaphane was further evidenced through the increased level of GSH, decreased accumulation of labile iron and lipid peroxides (4-hydroxy-2-nonenal, lipofuscin), decreased ferritinophagy and liver damage (decreased fibrosis, alanine aminotransferase, and aspartate aminotransferase). Finally, diabetes-induced increase in serum glucose and triglyceride level was significantly reduced by sulforaphane. Regardless of the fact that this study is limited by the use of one model of experimentally induced diabetes, the results obtained demonstrate for the first time that sulforaphane prevents diabetes-induced hepatic ferroptosis in vivo through the activation of Nrf2 signaling pathways. This nominates sulforaphane as a promising phytopharmaceutical for the prevention/alleviation of ferroptosis in diabetes-related pathologies. |
URI: | https://biore.bio.bg.ac.rs/handle/123456789/7095 | ISSN: | 0951-6433 1872-8081 |
DOI: | 10.1002/biof.2042 |
Appears in Collections: | Journal Article |
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